The MRL/Mp-Ipr/lpr (MRL/lpr) mouse strain spontaneously develops a systemic autoimmune disease which has striking resemblance to human SLE in its serological specificities and immunopathology. The genetic control of the disease in these mice is determined by the autosomal recessive lpr gene as well as by the background genes of the MRL strain. The current application will continue studies of the fundamental mechanisms involved in autoantibody production in the MRL/lpr mouse. It will target particularly the anti-Sm specificity, but will also study other autoantibodies and immunopathology. The proposed experiments will investigate the (molecular) genetic , cellular, stochastic, and environmental effects on disease expression. The grant is divided into five hypothesis-based Specific Aims. 1) Hypothesis: A large but restricted subset of immunoglobulin genes is utilized for the spontaneous anti-Sm response. The ongoing investigation of the V/H and V/L genes from anti-Sm hybridomas will be continued to understand the repeated use of certain V/H genes and the role of somatic mutation. 2) Hypothesis: The bimodal distribution of the anti-Sm response in MRL/lpr mice is due to the random generation of specific T-helper cells. Thymectomized, irradiated, bone-marrow-reconstituted chimeras will be utilized to determine the specificity of T cells for anti-Sm antibody formation. 3) Hypothesis: The critical influence of the MRL background genes on the generation of anti-Sm positivity is expressed at T-cell (or, alternatively, at the B-cell) level. Mixed chimeras of anti-Sm+ and anti-Sm-lpr mice will be used to elucidate the cellular level of control of anti-Sm formation by the MRL background genes. 4) Hypothesis: Environmental effects on the development of the immune system are irrelevant to the production of systemic autoimmunity in MRL mice. Germ- free and antigen-free MRL/lpr mice will be investigated for their autoimmune syndrome. 5) Hypothesis: The two murine class II loci (I-A and I-E) are not utilized equivalently in the generation of the anti-Sm response. The possibility that T-B collaboration restricted to particular class II loci or alleles results in specific immunopathological and serological manifestations of disease will be investigated. The accomplishments of these Specific Aims will result in important new information regarding the fundamental mechanisms of the immunoregulation of systemic autoimmunity in MRL/lpr mice and will thus allow us eventually to understand the parallel human syndrome of SLE. Only with such understanding will it be possible to design new rational therapeutic approaches.